Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that has become a global public health threat. The World Health Organization declared ZIKV and its suspected link to birth defects an international public health emergency on February 1, 2016. Epidemics of ZIKV infection have been reported in Mexico, and Central and South America and linked to cases of Guillain-Barre syndrome in adults and microcephaly in newborn infants in the setting of maternal infection during pregnancy. Despite the potential for infecting and causing disease in millions, specific diagnostics, treatments, or vaccines for ZIKV are not available. The primary goal of this collaborative and interactive project is to define the molecular, genetic, immunologic, characteristics of newly- isolated neutralizing human mAbs with broad specificity against all strains of ZIKV. A second goal is to define the mechanistic correlates of protection by neutralizing mAbs. A third goal is to determine whether cross-reactive anti-DENV human mAbs that bind to ZIKV are protective/therapeutic or pathogenic in a newly developed mouse model of ZIKV. We hypothesize that potently inhibitory mAbs recognize epitopes associated with key ZIKV structural transitions with high affinity and block one or more keys step during entry (e.g., attachment, entry, or fusion). Our approach will include high-efficiency isolation of human mAbs and with detailed functional and structural analyses to define how and why human mAbs inhibit ZIKV. We also will explore the significance of Fc?R binding and determine whether ZIKV is similar or different than DENV in the context of antibody-mediated immune enhancement of disease. In addition to fundamental studies of ZIKV pathogenesis and immunity, these studies also will result in the generation of a group of fully human mAbs that can be tested in preclinical models and could be developed rapidly as therapeutic or prophylactic biologic drugs for humans. Studies in this project also will inform ongoing diagnostic and future vaccine efforts against ZIKV, as they will define the principal major antigenic sites epitopes associated with potent type-specific antibody-mediated virus neutralization and protection. The collaborative multidisciplinary group assembled to conduct studies in this multi-PI application already collaborates productively, with a strong track record in studies of dengue, chikungunya and other arthropod-borne viruses, and has a clear division of labor for the studies proposed in this application.